Postdoctoral Fellowship: PRFB: Investigating the role of genome organization on de novo gene origination through cis- regulation

This action funds an NSF Postdoctoral Research Fellowship in Biology for FY 2024, Integrative Research Investigating the Rules of Life Governing Interactions Between Genomes, Environment, and Phenotypes. The fellowship supports the research and training of the fellow who will contribute to the area of Rules of Life in innovative ways. Some of the most fundamental questions in understanding the Rules of Life are: where do genes come from, and why do they evolve? This question is tackled by studies that identify and characterize genes that have recently appeared (in evolutionary terms) through the comparison of closely related species’ genomes. These studies show that while most newly evolved genes appear as duplicate copies of pre-existing genes, a small but important fraction of these genes appear to evolve de novo from regions of the genome that did not previously contain genes. As we currently have a relatively poor understanding of why different species make new genes from scratch, this research aims to test a new theoretical model explaining this process by examining the influence of the genome’s organizational structure on new gene birth. Prior models of de novo gene origination remain unsatisfying as they fail to explain the low likelihood of mutational processes driving 1) widespread, tissue-specific transcription and 2) the avoidance of post-translational decay of nascent polypeptides. The new cultivator model of de novo gene origination mitigates these problems by hypothesizing that the appearance of a new promoter provides a crude but rapid path toward modulating the expression of older, neighboring genes. This research has three primary components. This research first traces the evolutionary histories of de novo genes identified in Drosophila melanogaster while also producing a comparative evolutionary analysis of transcriptional control of spermatogenesis. The work then comprehensively characterizes the regulatory activity for extant, reconstructed ancestral, and synthetic de novo gene promoters in a high-throughput manner. This work will thus infer fundamental mechanisms of eukaryotic gene regulation. Finally, the work systematically screens for enhancer-promoter and promoter competition effects in de novo genes, revealing deeper insights into the interplay between enhancer and promoter elements. This work integrates the mentorship of a cohort of talented high school students from underrepresented backgrounds, first through weekly programming over the academic year, and then via one-on-one summer lab mentorship. This project also helps to increase neurodiversity and raise visibility for mental health issues in academia by establishing an easily accessible peer support network for those struggling with invisible difficulties. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.